Elizabeth H. Krenske

Aromatic Interactions as Control Elements in Stereoselective Organic Reactions

This Account describes how attractive interactions of aromatic rings with other groups can influence and control the stereoselectivity of many reactions. Recent developments in theory have improved the accuracy in the modeling of aromatic interactions. Quantum mechanical modeling can now provide insights into the roles of these interactions at a level of detail not previously accessible, both for ground-state species and for transition states of chemical reactions. In this Account, we show how transition-state modeling led to the discovery of the influence of aryl groups on the stereoselectivities of several types of organic reactions, including asymmetric dihydroxylations, transfer hydrogenations, hetero-Diels-Alder reactions, acyl transfers, and Claisen rearrangements. Our recent studies have also led to a novel mechanistic picture for two classes of (4 + 3) cycloadditions, both of which involve reactions of furans with oxyallyl intermediates. The first class of cycloadditions, developed by Hsung, features neutral oxyallyl intermediates that contain a chiral oxazolidinone auxiliary. Originally, it was thought that these cycloadditions relied on differential steric crowding of the two faces of a planar intermediate. Computations reveal a different picture and show that cycloaddition with furan takes place preferentially through the more crowded transition state: the furan adds on the same side as the Ph substituent of the oxazolidinone. The crowded transition state is stabilized by a CH-π interaction between furan and Ph worth approximately 2 kcal/mol. Attractive interactions with aromatic rings also control the stereoselectivity in a second class of (4+3) cycloadditions involving chiral alkoxy siloxyallyl cations. Alkoxy groups derived from chiral α-methylbenzyl alcohols favor crowded transition states, where a stabilizing CH-π interaction is present between the furan and the Ar group. The cationic cycloadditions are stepwise, while the Hsung cycloadditions are concerted. Our results suggest that this form of CH- π-directed stereocontrol is quite general and likely controls the stereoselectivities of other addition reactions in which one face of a planar intermediate bears a pendant aromatic substituent.

Transition states and energetics of nucleophilic additions of thiols to substituted α,β-unsaturated ketones: Substituent effects involve enone stabilization, product branching, and solvation

CBS-QB3 enthalpies of reaction have been computed for the conjugate additions of MeSH to six α,β-unsaturated ketones. Compared with addition to methyl vinyl ketone, the reaction becomes 1-3 kcal mol(-1) less exothermic when an α-Me, β-Me, or β-Ph substituent is present on the C=C bond. The lower exothermicity for the substituted enones occurs because the substituted reactant is stabilized more by hyperconjugation or conjugation than the product is stabilized by branching. Substituent effects on the activation energies for the rate-determining step of the thiol addition (reaction of the enone with MeS(-)) were also computed. Loss of reactant stabilization, and not steric hindrance, is the main factor responsible for controlling the relative activation energies in the gas phase. The substituent effects are further magnified in solution; in water (simulated by CPCM calculations), the addition of MeS(-) to an enone is disfavored by 2-6 kcal mol(-1) when one or two methyl groups are present on the C=C bond (ΔΔG(‡)). The use of CBS-QB3 gas-phase energies in conjunction with CPCM solvation corrections provides kinetic data in good agreement with experimental substituent effects. When the energetics of the thiol additions were calculated with several popular density functional theory and ab initio methods (B3LYP, MPW1PW91, B1B95, PBE0, B2PLYP, and MP2), some substantial inaccuracies were noted. However, M06-2X (with a large basis set), B2PLYP-D, and SCS-MP2 gave results within 1 kcal mol(-1) of the CBS-QB3 benchmark values.

Steric and Solvation Effects in Ionic SN2 Reactions

This paper explores the contribution of solvation to the overall steric effects of S(N)2 reactions observed in solution. The reactions of chloride ion with a series of alkyl chloronitriles, RCH(CN)Cl (R = methyl, ethyl, isopropyl, tert-butyl) were investigated both experimentally and theoretically. These reactions serve as a model system for the parent reactions, Cl(-) + RCH(2)Cl, which are too slow to measure. Each additional substitution at the beta-carbon lowers the reactivity, clearly demonstrating a steric hindrance effect. The magnitude of the steric effect, however, is not significantly different in the gas phase and in solution. We conclude that the solvation energies of the corresponding S(N)2 transition states must be similar regardless of size of the substituent. This lack of size dependence in the current system is in sharp contrast with many other ionic systems such as ionization of simple alkyl alcohols, where solvation depends strongly on size. We propose that the weak size dependence results from the compensation between a direct shielding effect of the substituent and an indirect ionic solvation effect, which arises from the geometric perturbations introduced by the substitution. The conclusion is further supported by calculations using polarizable continuum models and QM/MM simulations.

Origin of stereoselectivity in the (4 + 3) cycloadditions of chiral alkoxy siloxyallyl cations with furan

The mechanisms and stereoselectivities of (4 + 3) cycloadditions between chiral alkoxy siloxyallyl cations and furan are examined using density functional theory calculations. These cycloadditions are predicted to take place via stepwise mechanisms. The stereoselectivities of cycloadditions involving siloxyallyl cations derived from chiral alpha-methyl benzylic alcohols are controlled by two effects: minimization of steric repulsion between the alpha-Me group and the allyl group and attractive CH-pi interactions between the furan and the aryl group.

Stereoselectivity in oxyallyl–furan (4 + 3) cycloadditions: control of intermediate conformations and dispersive stabilisation in cycloadditions involving oxazolidinone auxiliaries

Chiral oxazolidinones were previously thought to control cycloaddition stereoselectivity by steric crowding of one face of the substrate. We have discovered that in (4 + 3) cycloaddition reactions of oxyallyls, the stereoinduction is caused instead by stabilising CH–π interactions that lead to reaction at the more crowded face of the oxyallyl. Density functional theory calculations on the (4 + 3) cycloadditions of oxazolidinone-substituted oxyallyls with furans establish unexpected transition state conformations and a new explanation of selectivity.

Catalytic Wittig Reactions of Semi- and Nonstabilized Ylides Enabled by Ylide Tuning†

The first examples of catalytic Wittig reactions with semistabilized and nonstabilized ylides are reported. These reactions were enabled by utilization of a masked base, sodium tert-butyl carbonate, and/or ylide tuning. The acidity of the ylide-forming proton was tuned by varying the electron density at the phosphorus center in the precatalyst, thus facilitating the use of relatively mild bases. Steric modification of the precatalyst structure resulted in significant enhancement of E selectivity up to >95:5, E/Z.

Stereoselectivities and regioselectivities of (4 + 3) cycloadditions between allenamide-derived chiral oxazolidinone-stabilized oxyallyls and furans: experiment and theory

A systematic investigation of the regioselectivities and stereoselectivities of (4 + 3) cycloadditions between unsymmetrical furans and a chiral oxazolidinone-substituted oxyallyl is presented. Cycloadditions were performed using an oxyallyl containing a (R)-4-phenyl-2-oxazolidinone auxiliary (2(Ph)), under either thermal or ZnCl(2)-catalyzed conditions. Reactions of 2(Ph) with 2-substituted furans gave syn cycloadducts selectively, while cycloadditions with 3-substituted furans gave selectively anti cycloadducts. The stereoselectivities were in favor of a single diastereoisomer (I) in all but one case (2-CO(2)R). Density functional theory calculations were performed to explain the selectivities. The results support a mechanism in which all cycloadducts are formed from the E isomer of the oxyallyl (in which the oxazolidinone C═O and oxyallyl oxygen are anti to each other) or the corresponding (E)-ZnCl(2) complex. The major diastereomer is derived from addition of the furan to the more crowded face of the oxyallyl. Crowded transition states are favored because they possess a stabilizing CH-π interaction between the furan and the Ph group.

Modular mesoionics: understanding and controlling regioselectivity in 1,3-dipolar cycloadditions of Münchnone derivatives.

1,3-Dipolar cycloadditions of mesoionic 1,3-dipoles (Münchnones, imino-Münchnones, and phospha-Münchnones) with alkynes offer versatile, modular synthetic routes to pyrroles. Reactivity and regioselectivity differ markedly for different members of this series, and we report here the first general rationale for differences in reactivity by means of a systematic investigation of 1,3-dipolar cycloadditions involving electron-poor and electron-rich alkynes. Competition kinetic measurements indicate that Münchnones and phospha-Münchnones are nucleophilic 1,3-dipoles that react most rapidly with electron-poor alkynes. However, the regioselectivities of cycloadditions are found to undergo an inversion as a function of alkyne ionization potential. The exact point at which this occurs is different for the two dipoles, allowing rational control of the pyrrole formed. The origins of these reactivities and regioselectivities are examined computationally. Frontier molecular orbital predictions are found not to be accurate for these reactions, but transition state calculations give correct predictions of reactivity and selectivity, the origins of which can be analyzed using the distortion/interaction model of reactivity. Cycloadditions with electron-poor alkynes are shown to favor the regioisomer that has either the most favorable TS interaction energy (Münchnones or imino-Münchnones) or the smallest TS distortion energy (phospha-Münchnones). Cycloadditions with more electron-rich aryl-substituted alkynes, on the other hand, generally favor the regioisomer that has the smaller TS distortion energy. These insights delineate the synthetically important distinctions between Münchnones and phospha-Münchnones: phospha-Münchnones undergo highly regioselective cycloadditions with electron-poor alkynes that do not react selectively with Münchnones, and the reverse is true for cycloadditions of Münchnones with electron-rich alkynes.

Opposing auxiliary conformations produce the same torquoselectivity in an oxazolidinone-directed Nazarov cyclization

Most applications of chiral oxazolidinone auxiliaries in asymmetric synthesis operate through a common set of stereocontrol principles. That is, the oxazolidinone is made to adopt a specific, coplanar conformation with respect to the prochiral substrate, and reaction occurs preferentially at whichever stereoheterotopic face is not blocked by the substituents on the oxazolidinone. In contrast to these principles, we report here the discovery of an alternative mechanism of oxazolidinone-based stereocontrol that does not require coplanarity and is driven instead by allylic strain. This pathway has been uncovered through computational studies of an asymmetric Nazarov cyclization. Chiral oxazolidinone auxiliaries provide essentially complete control over the torquoselectivity of ring closure and the regioselectivity of subsequent deprotonation. Density functional theory calculations (M06-2X//B3LYP) reveal that in the transition state of 4π electrocyclic ring closure, the oxazolidinone ring and the cyclizing pentadienyl cation are distorted from coplanarity in a manner that gives two transition state conformations of similar energy. These two conformers are distinguished by a 180° flip in the auxiliary orientation such that in one conformer the oxazolidinone carbonyl is oriented toward the OH of the pentadienyl cation (syn-conformer) and in the other it is oriented away from this OH (anti-conformer). Surprisingly, both conformations induce the same sense of torquoselectivity, with a 3-5 kcal/mol preference for the C5-β epimer of the ring-closed cation. In both conformations, the conrotatory mode that leads to the C5-α epimer is disfavored due to higher levels of allylic strain between the oxazolidinone substituent and adjacent groups on the pentadienyl cation (R(4) and OH). The excellent torquoselectivities obtained in the oxazolidinone-directed Nazarov cyclization suggest that the allylic strain-driven stereoinduction pathway represents a viable alternative mechanism of stereocontrol for reactions of sterically congested substrates that lie outside of the traditional coplanar (N-acyloxazolidinone) paradigm.

Theoretical Investigation of the Mechanisms and Stereoselectivities of Reductions of Acyclic Phosphine Oxides and Sulfides by Chlorosilanes

Computational studies were performed to explain the highly varied stereoselectivities obtained in the reductions of acyclic phosphine oxides and sulfides by different chlorosilanes. The reductions of phosphine oxides by HSiCl(3), HSiCl(3)/Et(3)N, and Si(2)Cl(6) and the reductions of phosphine sulfides by Si(2)Cl(6) (all in benzene) were explored by means of B3LYP, B3LYP-D, and SCS-MP2 calculations. For the reductions of phosphine oxides by HSiCl(3), the calculations support the mechanism proposed by Horner in which a hydride is transferred from silicon to phosphorus through a four-centered, frontside transition state. This mechanism leads to retention of stereochemistry at phosphorus. For the other three reductions, two classes of mechanisms were explored. Phosphorane-based mechanisms that were previously proposed by Mislow and involve SiCl(3)(-) were compared with novel alternative mechanisms that involve nonionic rearrangement processes. In one of these, donor-stabilized SiCl(2) is formed as an intermediate. The calculations support a phosphorane-based mechanism for the reductions of phosphine oxides by HSiCl(3)/Et(3)N and Si(2)Cl(6) (which proceed with inversion) but favor the rearrangement pathways for the reductions of phosphine sulfides by Si(2)Cl(6) (which proceed with retention).